Device for measuring volume of drug

ABSTRACT

A drug delivery device having a housing containing a gas generator controlled by an electronic controller. The gas generator generates gas into a reciprocable chamber, whereby reciprocation of the chamber causes a lever to reciprocate a pawl, and this action causes a ratchet to The device may also be provided with manually control for delivering a bolus dose of drug when necessary.

[0001] This invention relates to drug delivery devices, and inparticular to portable devices designed to be carried by a patientduring normal activities.

BACKGROUND OF THE INVENTION

[0002] A number of drug delivery devices are known in which medicamentis driven from a reservoir, under the action of a driving mechanism,through a needle and into the skin of a patient. A problem with knowndevices is that the delivery rate accuracy suffers when the volume ofdrug is small. Such inaccuracies arise in many cases from the drivingmechanisms employed which give rise to variations in delivery rates. Forexample, where a gas is generated to drive a plunger in a cartridge orvial, the volume of gas depends in part on the temperature of theenvironment. The variation in volume will also depend on the totalamount of gas already present in the chamber.

[0003] The reason that gas generation is preferred over mechanicaldriving mechanisms is that the design of gas generating cells, such aselectrolytic cells' is extremely simple when compared to mechanicalequivalents, and this provides significant advantages in terms ofreliability and cost-effectiveness. Systems are known in which amechanically driven ratchet is used to incrementally deliver fixedamounts of medicament, but such systems can be expensive to manufacture.In particular, the accuracy of delivery of small amounts of drug dependson the manufacturing tolerances of the ratchet mechanism. Formass-produced, moulded, cut or pressed ratchets, the tolerances may notbe sufficiently accurate to deliver the required small volumes, whichmeans that more expensive manufacturing techniques are required toobtain the necessary tolerances. Such considerations are particularlyimportant if the devices are intended to be disposable, in which case alow unit cost is required without compromising accuracy or reliabilityor system performance.

[0004] A problem with gas driven mechanisms, however, is that it isextremely difficult to ensure that a gas chamber is leakproof withouttaking elaborate manufacturing and quality control precautions. Even ifa leak is minor and relatively slow, this poses a real problem when themechanism is supposed to accurately deliver small volumes over extendedtimespans. Thus, for gas generation systems, it is preferred to design asystem that is leak free (which is costly and typically more complex) orprovide a system that functions accurately in spite of minor orrelatively slow leaks. In the alternative, gas generation may not besuitable for lower delivery rates. As mentioned above, mechanicalequivalents having the required precision (e.g. clockwork mechanisms)are overly expensive and complex for incorporation into inexpensivedevices which may be disposable.

[0005] For many drug delivery regimes, it is desirable to provide bothsteady state delivery (“basal delivery”) and instantaneous bursts ofdrug (“bolus delivery”) as required. In particular, in patientcontrolled analgesia or PCA, it may be advantageous to provide acontinuous basal infusion of drug for chronic pain treatment,supplemented to a certain extent by bolus delivery. The bolus deliverywould be activated by the patient to deal with increased temporary painlevels (“break-through pain”), with safeguards being incorporated toprevent overdosing.

[0006] Another area in which precisely controlled dosing can beparticularly indicated is in chronotherapeutic drug delivery, in whichthe drug delivery rate varies over time. Most notably, diurnal orcircadian rhythms cause variations in the amounts of certain drugsrequired by a patient during a 24-hour period. This is most notablyrequired to combat variations in disease and/or condition effectsthroughout a 24-hour cycle.

[0007] For example, hypertension crises, angina, and sudden cardiacdeath are most likely to occur in the morning, whereas sickle cellcrises and perforated ulcer crises are most likely to occur in theafternoon. The concept of chronotherapeutics is discussed in more detailin an article by Smolensky & Labrecque, Pharmaceutical News 4, No. 2,1997, pp. 10-16. The discussion in this article is principally in termsof conventional oral dosing of drugs to take account ofchronotherapeutic variations in drug uptake, effects, and requirements,but many of the principles are applicable to other delivery routes.Circadian rhythm applications would also apply to hormonal therapies.

[0008] Accordingly there is a need to provide a drug delivery devicecapable of regulating drug delivery dosages to provide increased dosagesat the times when such dosages are more likely to be required. Thisgives rise to a need for a device in which the delivery rate isaccurately controllable over a wide range of delivery rates. In general,devices which are designed to deliver small amounts of drug are notparticularly suitable for high drug delivery rates without beingspecifically adapted in this regard, and vice versa. Moreover there is aneed to provide such a device that is relatively compact so that it isfixed to the user during use and disposed of when the treatment isfinished. Such a device must be also relatively inexpensive tomanufacture yet maintain accurate and reliable delivery rates.

[0009] The present invention aims to provide improved drug deliverydevices in which smaller volumes of liquid can be delivered moreaccurately than in prior art devices, thereby giving rise to overallmore controlled delivery rates. The invention also aims to provide suchdevices which additionally allow higher delivery rates to be provided ondemand, up to and including bolus delivery. Moreover, the presentinvention provides for a drug delivery device wherein the technologyused to provide for accurate delivery rates is relatively easy andinexpensive to manufacture. Further, the present invention employsdesigns for the gas generating system and delivery system so that spacewithin the device is minimised and parts used within the device are easyand inexpensive to manufacture while maintaining high tolerances. Inaddition, the present invention provides for a certain amount of gasleakage while delivering accurate dosages. This eliminates the need forcostly sealing devices and systems which increase cost and decreasereliability in the event of gas leakage.

SUMMARY OF THE INVENTION

[0010] The invention provides a drug delivery device having a housingcontaining a drug reservoir, and means for facilitating the expulsion ofdrug from the drug reservoir. The device also includes a mechanism incommunication with the facilitation means, that incrementally advancesand thereby drives the drug from the reservoir, and a member associatedwith the mechanism to cause the incremental advancement of the mechanismas the member moves in a first direction. The device also includes a gasgenerator located within the housing and operable to expand in achamber. The member is in transmission relation to the chamber. Inoperation, the member is driven by the movement of the chamber toadvance the mechanism and thereby drive the drug from the reservoir inincremental fashion.

[0011] Preferably, the mechanism in communication with the facilitationmeans comprises a ratchet.

[0012] Further, preferably, the member moves in a reciprocable fashion.

[0013] Further, preferably, the movement of the reciprocable membercauses the stepwise advancement of the mechanism.

[0014] Further, preferably, the reciprocable member is connected to awall of the chamber, whereby the reciprocation of the reciprocablemember is driven by the expansion and contraction of the chamber.

[0015] The preferred devices according to the invention take advantageof the reciprocation of a gas generation chamber to effect a stepwiseadvancement of a ratchet mechanism. Gas generation chambers which expandand contract repeatedly are advantageous over known chambers whichsimply expand over time. For example, a ratchet which has 100 teeth andis driven by a continuously expanding gas chamber will advance one stepfor every 1% increase in the chamber volume. According to basic gaslaws, a temperature rise of only 3° C. will increase the volume of a gasat room temperature by 1%. Thus, towards the end of the chamberexpansion, a temperature rise of 3° C. will drive the ratchet one stepforward independently of the gas generation rate. In contrast, a chamberwhich reciprocates will undergo a full expansion for each stepwiseadvance of the ratchet mechanism, and a 1% variation in the volume ofthis chamber will have no material effect on the fact that the chamberwill expand fully and advance the ratchet correctly.

[0016] For example, a ratchet mechanism which undergoes 100 stepwiseadvances throughout the emptying of a reservoir. If this ratchet isdriven by a continuously expanding gas chamber, a 1% increase in thevolume of gas towards the end of the delivery period will advance theratchet by an (undesired) extra step. Such a 1% expansion occurs with atemperature change of only 3° C. (which is approximately 1% of the roomtemperature when expressed in kelvins). The situation is worse fordevices which require several hundred ratchet advances to ensure thenecessary sensitivity for accurate delivery over an extended timeperiod.

[0017] In contrast, devices according to the present invention employ areciprocating chamber which continually expands and contracts. Thisenables small-volume chambers to be employed such that the difference involume between the contracted and expanded states is orders of magnitudegreater than the change in volume arising from environmental temperaturechanges. Moreover, by employing a reciprocating chamber, less space isneeded for the chamber as the volume at maximum expansion isconsiderably less that what would be required for a continuouslyexpanding chamber at the maximum volume of expansion.

[0018] Preferably, the chamber is elastically biased to revert to acontracted state, and wherein a venting means is provided to enablecontraction of the chamber after gas generation has expanded thechamber.

[0019] One advantage of using a reciprocity chamber to drive areciprocating mechanism linked to a ratchet is that there is sufficientamplitude of movement in the reciprocation to advance the ratchet by therequired number of steps (in many cases only one step), to ensure thatventing is sufficiently thorough to relax the system completely, inorder to arrive at a device in which the delivery rate is controlled toa high degree of accuracy.

[0020] For example, if the delivery volume is low (equivalent to asingle stepwise ratchet advance) every five minutes, then the gasgenerator can be designed to deliver a sufficient amount of gas withinone minute, and then switch off automatically for four minutes. In thefirst minute, the ratchet will be caused to advance by the required“tooth” (or equivalent), and then the venting means is actuated to relaxthe system. By the end of four minutes the system will be fully relaxedand the cycle can begin again.

[0021] This design automatically compensates for any inaccuracies in theperformance of its driving mechanism. Thus, the gas generator can bedesigned to deliver e.g. 20%±10% more than the required volume of gas(i.e. not a particularly expensive or accurate system), and still tohave an extremely accurate delivery for the following reason. If the gasgenerator generates between 10% and 30% too much gas on each cycle, theratchet will advance by a single “tooth”, but it is equally certain thatit will not be pushed to advance by a second tooth. Thus, when the gasgeneration ceases, a certain amount of controlled overpressure or stresswill be present in the system, but the amount of drug delivered will beprecisely known. Then when the gas is vented, the overpressure isreleased and the system returns to equilibrium. Thus, the accuracy ofdelivery at the end of the five minute cycle is independent of whetherthe generator generated 10% or 30% too much gas.

[0022] It should be noted that the accuracy of the system is controlledby the tolerances of the ratchet mechanism, the timer, the reciprocitychamber, the venting system and the gas generator.

[0023] In some embodiments, the venting means is passive and allowsescape of gas therethrough when the chamber is pressurised relative toatmospheric pressure. In other embodiments, there is designed to beventing means within the gas generator. Such venting means may connectsub-chambers within the gas generating means. The venting means enablesthe sub-chambers to increase and decrease pressure therein moreefficiently.

[0024] In some embodiments, the gas generator is adapted to generate gasat a rate higher than the venting rate. When the gas generator isactive, the chamber becomes pressurised and expands, and when the gasgenerator is inactive, the venting means causes depressurisation andcontraction of the chamber. Minor leaks in the system, provided thatthey are not so serious as to prevent the chamber from fullypressurising, do not have any significant effect on the operation oraccuracy of the device. This enables a gas generating system to deliverextremely small volumes of drug in a highly controlled, accurate manner,without employing any elaborate gas generation system, or any specialleakproofing of the gas chamber. Also, the gas generation rate shouldexceed the venting rate so that the error of movement of thereciprocator member errs to the side of excessive pressure rather thantoo little pressure. If there is insufficient pressure (i.e. caused bythe leakage rate exceeding the pressurisation rate, the force needed tomove the reciprocating member will be insufficient and the pawl on theratchet will not move. Thus, the volume of drug will not be advancedthrough the cartridge and delivered to the user.

[0025] In alternative embodiments, the gas pressure of the gas generatoris divided between at least two cells. A first cell has a more permeablemember and is designed for minimum gas leakage. The first cell also hasa controllable vent associated therewith. The vent allows excess gas toescape from the first cell but prevents the escape of gas at a stage inthe cycle when the member of the first cell is needed to deflect so asto cause forward movement of the ratchet. The alternative embodiment isalso designed so that the latter part of the cycle allows the re-openingof the first cell vent to enable gas therein to quickly escape and causethe member to return to its initial resting position.

[0026] In some preferred embodiments, the venting means comprises apermeable or semi-permeable member. Currently one of the most preferredmember is a silicone membrane. In another embodiment, there are at leasttwo members with varying permeability. The less permeable material ispreferably bromo-butyl, ethylene propylene or EPDM, and the morepermeable member is preferably silicone rubber.

[0027] Suitably, the mechanism is caused to advance as the chamberundergoes expansion. Alternatively, the mechanism may be caused toadvance as the chamber undergoes contraction. While it is possible toemploy a mechanism which drives the ratchet forward during bothexpansion and contraction strokes, it is preferred to employ a singledriving stroke (either contraction or expansion) during a reciprocationcycle for lower delivery rates.

[0028] Suitably, the member comprises a lever extending between thechamber and the mechanism.

[0029] The use of a lever mechanism enables the amplitude of movement ofthe expanding chamber to be accurately converted to the correctamplitude of movement to drive the ratchet.

[0030] In certain preferred embodiments, the mechanism comprises a rigidratchet element having spaced formations on a surface thereof.

[0031] Preferably, the formations have a sawtooth cross section,although the formations may be in the form of grooves on a surface ofthe rigid ratchet element.

[0032] Preferably, the mechanism includes a pawl carried on the member,the pawl being adapted to make ratcheting engagement with the formationson the rigid ratchet element.

[0033] Further, preferably, the pawl is resiliently biased against theformations on the rigid ratchet element.

[0034] Suitably, the pawl is in the form of a substantially flat springan end of which bears against the formations on the rigid ratchetelement.

[0035] Such a pawl is adapted to allow the ratchet element to slide withlittle resistance in one direction but to prevent any movement in theopposite direction.

[0036] In preferred embodiments, the formations are regularly spacedalong the rigid ratchet element, and the pawl comprises a pair of pawlmembers resiliently biased against the rigid ratchet element atdifferent points along the length of the rigid ratchet element, theaxial distance between the pair of pawl members being different to theaxial distance between successive formations.

[0037] The advantage of this arrangement is that by locating theratcheting linkage between the pawl and the ratchet teeth, the teethmake alternating contact with either pawl member. The ratcheting memberadvances by increments which are less than the actual difference betweensuccessive formations on the ratchet.

[0038] In particularly preferred embodiments, the distance betweensuccessive formations is twice the distance between the pawl members.This means that then the ratchet advances in half steps and enablesaccurate delivery of even smaller incremental volumes of drug (if a fullstep is counted as equating to the distance between successive ratchetteeth formations.)

[0039] The definitions of “half steps” and “full steps” is not asarbitrary as it may appear, since one of the main constraints on theaccuracy of delivery of small volumes, as explained above, is themanufacturing tolerances of the ratcheting teeth.

[0040] It is envisaged that one of the least expensive ratchetingmechanisms, and therefore one of the most suitable for large scaleproduction, is a stamped plastics ratchet bar having a sawtooth surface,against which a pawl in the form of a leaf spring may be biased. Themain limitation on accuracy in this system is likely to arise from thespacing of adjacent sawtooth formations which may not be able to be madeaccurately with the required spacing. In such cases the minimum deliveryvolume, all other things being equal, will be limited by this component.However, by employing a specially designed pawl or leaf spring (whichcan be made to much higher tolerances from metal materials at relativelylow cost), accuracy is doubled, and the minimum deliverable volume maybe halved.

[0041] In alternative embodiments, the ratchet teeth are regularlyspaced along the rigid ratchet element, and the pawl comprises three ormore members resiliently biased against the rigid ratchet element atregular intervals along its length. The axial distance between eachsuccessive pair of pawl members is chosen to be different to the axialdistance between successive ratchet teeth.

[0042] Suitably, in such cases, the distance between successive ratchetteeth is given by the number of pawl members multiplied by the distancebetween each successive pair of pawl members.

[0043] Thus, by analogy with the two pawl members spaced at half of thedistance between successive ratchet teeth, three or four pawl memberswould preferably be spaced at intervals of a third and a quarter,respectively, of the distance between successive ratchet teeth on theratchet element.

[0044] Suitably, the pawl is in the form of a resilient member whichterminates in a plurality of fingers biased against the ratchet element.

[0045] A preferred embodiment in this regard is a pawl which comprises aflat spring which is partly split to define fingers of differentlengths.

[0046] In another preferred embodiment, the ratchet element comprises ahelical spring and the pawl comprises one or more fingers which engagewith the coils of the spring. The coils of a helical spring easilyengage with the pawl fingers, and the regular spacing of the coils of ahelical spring enable it to be used as a ratchet element.

[0047] A further advantage of this embodiment is that the size of thedevice can be minimised by taking advantage of the flexibility of thespring. Thus, whereas a rigid ratchet bar protruding from a drugcartridge before use might provide an unacceptably long device forcertain applications (after use, the ratchet element might be partly ortotally accommodated within the empty cartridge interior), a helicalspring can be bent to be parallel with the cartridge to reduce theoverall length.

[0048] Preferably, in embodiments which employ a helical spring in lieuof a ratchet element, one or more fixed fingers are mounted in fixedposition relative to the housing, and one or more reciprocable fingersare mounted on the mechanism, such that when the one or morereciprocable fingers move in a first direction they engage the coils ofthe helical spring to drive the helical spring in the first direction,and when the one or more reciprocable fingers move in an oppositedirection, the one or more fixed fingers engage with and hold the coilsof the helical spring preventing it being driven back in the seconddirection, whereby the fixed and reciprocable fingers co-operate todrive the helical spring in one direction only.

[0049] The operation of this embodiment will become clearer from thedescription below. The fingers are generally arranged such that thehelical spring is forced to alternately slip past the fixed fingers andthe reciprocable fingers, which gives rise to a uni-directional drivingmovement. Suitably, each finger is inclined in the first direction. Thismakes it easier for the helical spring coils to slip past the fingers inthis direction, and more difficult for the coils to push back in theopposite direction against the fingers.

[0050] Preferably, the position of the one or more fixed fingersrelative to the one or more reciprocable fingers is such that thehelical spring is driven by the reciprocable fingers towards the fixedfingers.

[0051] This feature helps prevent a situation which may develop in whicha flexible helical spring is pulled by the reciprocable fingers awayfrom the fixed fingers, but rather than slipping past the fixed fingers,the helical spring merely stretches, such that when the reciprocatingfingers move back towards the fixed fingers the helical spring simplyrelaxes, without any net movement having taken place. The solution tothis problem is achieved in part by pushing the helical spring towardsthe fixed fingers as the driving step of the delivery action.

[0052] Suitably, the minimum distance between the fixed and reciprocablefingers, respectively, is not greater than ten times the distancebetween adjacent coils of the helical spring when the helical spring isin a relaxed position. Preferably, this minimum distance between thefixed and reciprocable fingers, respectively, is not greater than fivetimes the distance between adjacent coils of the helical spring when thehelical spring is in a relaxed position, most preferably not greaterthan twice the distance between adjacent coils.

[0053] The reason for this again relates to the problem of using aflexible spring which is likely to stretch rather than be displaced.While the problem could be overcome by using a sufficiently stiffspring, this would defeat the purpose of using this type of spring,which is to allow the ratchet element to be bent within the housing toreduce overall dimensions. While even a stiff spring can be bent undersufficient force, this tends to generate frictional forces which wouldprevent the spring from sliding past the ratchet fingers.

[0054] Instead, setting the two sets of fingers close together allowseven a relatively very flexible spring to be used without muchstretching, since for a given overall amount of stretching, a greaterstiffness is achieved by concentrating this stretching over just a fewcoils.

[0055] Thus, in certain preferred embodiments, the minimum distancebetween the fixed and reciprocable fingers, respectively, isapproximately equal to the distance between adjacent coils of thehelical spring when the helical spring is in a relaxed position.

[0056] Suitably, the mechanism comprises a flexible ratchet elementwhich is sufficiently stiff to drive medicament from the chamber whendriven by the member, and sufficiently flexible to be bent before itmeets the member, whereby the overall length of the device is reducedrelative to a device in which a rigid ratchet element protrudes linearlyfrom the mechanism before use. Thus, the flexible member may be, forexample, a piece of bendable thermoplastics stamped or molded with aratchet sawtooth profile.

[0057] In order for this embodiment to be useful, the flexible membershould have a degree of flexibility which allows it to be bentsufficiently to reduce the overall dimensions of the device.Furthermore, it must nevertheless be sufficiently stiff to transmit thedriving force of the ratcheting mechanism without buckling or distortingto any great extent. This can be achieved by restraining the degree offreedom of movement of the member.

[0058] For example, by driving a flexible member into a conduit in whichthe flexible member makes a good fit, the flexible member is preventedby the conduit walls from bowing or buckling sideways. Thus, when drivenby the ratchet mechanism the flexible member is constrained to transmitthe driving force to the piston, and despite its flexibility it acts asa drivable piston rod. Other mechanisms not requiring a restrainingconduit are also possible, as described below.

[0059] Preferably, the mechanism comprises two or more co-operatingflexible ratchet elements which are individually sufficiently flexibleto be bent before they meet the member but when joined together aretogether sufficiently stiff to drive medicament from the chamber whendriven by the member.

[0060] Further, in a preferable embodiment, the two or more co-operatingflexible ratchet elements are bent away from one another before theymeet the member.

[0061] Suitably, the device according to the invention further compriseselectronic control means for controlling the delivery rate. Preferably,the electronic control means comprises a timing mechanism whichalternately energises and de-energises the gas generating mechanism forcontrolled periods.

[0062] As explained above, by choosing an energized period long enoughto always guarantee complete advancement of the ratchet mechanism by apredetermined number of steps, and by providing a de-energised period(e.g. for venting) which allows relaxation of the system, the amount ofdrug delivered in this overall cycle is accurately controllableindependently of variations (within reason) in the gas generation rate.

[0063] Furthermore, the use of a timer allows the overall cycle lengthto be varied in a controlled manner over time, thereby providing anaccurately controllable device which delivers at a time-varying rate.Such devices find a particular application in the field ofchronotherapeutics.

[0064] Further, preferably, the electronic control means is programmablefor different delivery programs. The control means may beuser-programmable or a single unit may be factory-programmable fordifferent delivery regimes (e.g. for different drugs. Preferably, thedevice according to the invention further comprises means for manuallyadjusting the delivery rate. This allows for a certain degree offlexibility which might be desirable where the user can safely have anamount of control over the treatment. Alternatively, it can be set bythe physician or pharmacist and disabled to prevent patientinterference.

[0065] In preferred embodiments, the member reciprocates to cause theincremental advancement of the mechanism and the means for manuallyadjusting the delivery rate comprises means for limiting the travel ofthe member, whereby the volume of drug delivered on each reciprocatingstroke is controllable. Thus, a simple advancing screw can control astop against which any reciprocating element ends its travel. If this isused, adjustment of the screw will provide a control mechanism. Forexample, a device could be designed with three delivery rates, namelylow, medium and high, corresponding respectively to one, two and threeratchet advancements per reciprocation. A simple mechanism woulddetermine how far the reciprocating mechanism is allowed to advance oneach stroke, to determine the delivery rate. Clearly, more sophisticatedembodiments could also be achieved. Devices having the ability todeliver bolus doses of drug are preferred in therapies such as patientcontrolled analgesia.

[0066] In a preferred embodiment, the means for manually adjusting thedelivery rate provides the user with the ability to deliver a bolus doseof drug. It is advantageous if the bolus dose can be delivered withoutthis interfering with the normal basal delivery rate.

[0067] When the reciprocating mechanism comprises a lever arrangement,it is preferred that the means for manually advancing the mechanismcomprises means for manually advancing the lever extending between thechamber and the mechanism, operable from the exterior of the housing.Any suitable mechanism, such as a knob, button or lever can be used tooperate the lever.

[0068] Preferably, the mechanism comprises a ratchet and wherein themeans for manually advancing the mechanism comprises a pawl which ismanually reciprocable from the exterior of the housing.

[0069] Further, preferably, the mechanism for manually advancing saidlever is provided with gradations corresponding to a number of stepwiseadvances of the ratchet mechanism.

[0070] For example, in delivering insulin, the advancing means could bemarked in units which would be understood by the patient, and the scalewould be calibrated to correspond to the delivery of the correct dose.

[0071] In a further aspect, the present invention provides a method ofdelivering drug to a patient. The method includes affixing a drugdelivery device to the surface of the patient's skin. The drug deliverydevice having a housing containing a drug reservoir, means forfacilitating expulsion of drug from the drug reservoir, a mechanism incommunication with the facilitation means, operable to undergoincremental advancement and thereby drive the drug from the reservoir, amember operatively associated with the mechanism to cause theincremental advancement of the mechanism as the member moves in a firstdirection, and a gas generator located within the housing and operableto expand in a chamber, the member being in transmission relation to thechamber. The method further includes activating the device whereby themember is driven by the movement of the chamber to advance the mechanismand thereby drive the drug from the reservoir in incremental fashion.

[0072] Other objects, features and advantages of the present inventionwill become apparent upon reading the following detailed description,when taken in conjunction with the drawings and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0073] The invention will be now be described with reference to theaccompanying drawings, which illustrate the preferred embodiments of thepresent invention and in which:

[0074]FIG. 1 is a sectional plan view of a first embodiment of a drugdelivery device according to the invention;

[0075] FIGS. 2-5 are schematic views of a detail of the embodiment ofFIG. 1 shown at successive points in the operating cycle;

[0076]FIG. 6 is a sectional plan view of the embodiment of FIG. 1, inuse;

[0077] FIGS. 7-11 are sectional side views of a second embodiment of adevice according to the invention, shown at successive points during itsuse;

[0078]FIG. 12 is a simplified sectional plan view of a third embodimentof a drug delivery device according to the invention;

[0079]FIG. 13 is a cross sectional side view of the embodiment of FIG.12, taken along the line XIII-XIII;

[0080]FIG. 14 is a sectional plan view of a fourth embodiment of a drugdelivery device according to the invention;

[0081]FIG. 15 is a cross sectional side view of the embodiment of FIG.12, taken along the line XV-XV;

[0082]FIG. 16 is a graph showing the test results of an 80 hour testwhich plots delivery pressure and amount of drug delivered against time;

[0083]FIG. 17 is an enlarged detail of a portion of the graph of FIG.16;

[0084]FIG. 18 is a sectional plan view of a fifth embodiment of a drugdelivery device according to the invention;

[0085]FIG. 19 is a sectional side view of the embodiment of FIG. 18;

[0086]FIG. 20 is a sectional plan view of the embodiment of FIG. 18, asit is being prepared for use;

[0087]FIG. 21 is a sectional side view of the embodiment of FIG. 18 whenready for use;

[0088]FIG. 22 is a sectional plan view of a sixth embodiment of the drugdelivery device according to the invention;

[0089]FIG. 23 is a sectional plan view of the embodiment of FIG. 22 whenready for use;

[0090]FIG. 24 is a cross-sectional view along line A-A of the embodimentof FIG. 22;

[0091]FIG. 25 is a cross-sectional view along line B-B of the embodimentof FIG. 22; and

[0092]FIG. 26 is a schematic drawing representing the various parts ofthe gas generation sub-assembly of the embodiment of FIG. 22.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0093] Referring now in more detail to the drawings, in which likenumerals indicate like parts throughout the several views, in FIG. 1there is indicated, generally at 10, a drug delivery device according tothe invention. The device 10 comprises a housing 11 containing acartridge 12 filled with a drug 13. The cartridge 12 is provided with aneedle 14 extending from a first end 15 of the cartridge for delivery ofdrug 13 to a patient. A piston 16 is slidably received in the cartridge12, such that when the piston 16 is pushed towards the first end 15,drug is forced from the cartridge 12 out through the needle 14.

[0094] The piston 16 is mounted on a ratchet bar 17 which is driven by apawl 18 mounted on a reciprocable lever 19. Lever 19 is mounted on anaxis 20 at one side 21 and is connected to a driving rod 22 at the otherside 23, whereby reciprocation of the driving rod 22 causes pawl 18 toreciprocate with respect to the ratchet bar 17. As will be explained ingreater detail below, this causes the ratchet bar 17 to advance stepwisetowards the first end 15 of cartridge 12 and thereby drive the drug 13from the cartridge.

[0095] The driving rod 22 is in connection with a flexible diaphragm 24which defines a wall of a gas generation chamber 25. A battery 26 isconnected via a microprocessor 27 to an electrolytic cell 28 which isoperable to generate a gas into chamber 25. When gas is generated, thechamber expands and causes the diaphragm 24 to move. This movementpushes the driving rod 22 in the direction away from the first end 15 ofcartridge 12. The movement is opposed by a return spring 29 which biasesthe lever 19 towards the first end 15. After a certain period of timethe chamber 25 is fully expanded and the supply of current from thebattery 26 to the electrolytic cell 28 is switched off by themicroprocessor 27.

[0096] A silicone membrane 30 defines a wall of the chamber 25. Themembrane 30 is slightly permeable and thus allows a controlled leakageof gas from the chamber 25. When the chamber 25 is in its expandedstate, the force of return spring 29 will act to decompress the chamber25 by gas leaking through membrane 30. After the chamber 25 has fullydecompressed in this manner, the lever 19 and hence the pawl 18 willhave made one complete reciprocation thereby advancing the ratchet bar17 by a fixed step.

[0097] For example, the cycle might be chosen to allow the delivery of aquantity of drug corresponding to the advancement of a single step ofthe ratchet bar 17 every five minutes. In such a case the electrolyticcell 28 could be switched on for one minute and then switched off forfour minutes. As long as the timing of the microprocessor is accurate,this will ensure that precisely one stepwise advance is made in thatfive minute period.

[0098] The precision of device 10 is to a certain extent independent ofthe exact quantity of gas generated because the ratchet bar 17 isquantised, i.e. it can only move by a fixed step (or number of steps) ata time. Similarly, because the membrane 30 provides a controlledconstant leakage from the system even during gas generation, other minorleaks which might affect the accuracy of conventional gas drivendelivery devices are not important (although of course if the leak isbad enough the chamber will be unable to pressurise fully when the gasis generating).

[0099] It will be noted from the first embodiment shown in FIG. 1 thatpawl 18 is split in two halves, i.e. a longer half 31, and a shorterhalf 32. The pawl 18 is a leaf spring which is biased down onto ratchetbar 17. The halves 31,32 of the pawl 18 are of unequal length.

[0100]FIG. 2 shows a cross-sectional enlarged view of a portion of theratchet bar 17 which has a series of evenly spaced steps or teeth 33,34.The difference in length between the halves 31,32 of the pawl 18 isexactly half of the distance between adjacent teeth 33,34 on the ratchetbar 17. It can be seen that each tooth 33,34 has a sloped surface 35having a peak 36 and a trough 37, as shown in detail in FIG. 2A. At thepoint of the cycle illustrated in FIG. 2, the longer half 31 of the pawl18 presses against the sloped surface 35 of tooth 33, midway between thepeak 36 and trough 37, and the shorter half 32 presses against thetrough 37 of the adjacent tooth 34.

[0101] When gas is generated to drive the driving rod 22 in thedirection away from the first end 15 of cartridge 12 (see FIG. 1), thetwo halves 31,32 of the pawl extending from lever 19 (FIG. 1) move leftas viewed in FIG. 2. This results in the situation shown in FIG. 3, inwhich the shorter half 32 has been pushed back up the sloped surface 35of tooth 34, and the longer half 31 has passed the peak 36 of tooth 33to rest in the trough 37 of adjacent tooth 34 formerly occupied by theshorter pawl half 32. In practice, the distance travelled by the pawl 18will be slightly further than the minimum necessary so as to allow forany variations between components. This does not affect the operation ofthe invention as a whole since the pawl 18 when making its return strokewill press against the correct tooth as it begins its travel.

[0102] After the gas generation chamber 25 is pressurised fully and thedevice 10 is in the FIG. 3 position, gas generation ceases and thecontrolled leakage from the chamber 25 allows the return spring 29 topush the lever 19 back to its starting position, leading to theconfiguration shown in FIG. 4.

[0103] In FIG. 4, the longer pawl half 31 when being driven forward(i.e. to the right) has abutted against tooth 33 and pushed the ratchetbar 17 forward. This completes one reciprocation of the pawl 18, andwhen the electrolytic cell 26 again fills the gas generation chamber 25to drive the pawl 18 to the left (as seen in FIG. 5), the short pawlhalf 32 passes over the peak 36 of tooth 34 as shown in FIG. 5, ready topush against tooth 34 and thereby once again advance the ratchet bar 17.

[0104] The reason for using a pawl in two halves of unequal length isseen by observing the movement of a point 38 on the ratchet bar. After acomplete cycle has been completed, i.e. from FIG. 2 to FIG. 5, the point38 has moved by a distance 1/2 L. This is exactly half of the length Lof one of the teeth 33,34 on the ratchet bar 17, as can be seen withreference to FIG. 2A.

[0105] In effect this means that although the manufacturing quality andtolerances are such that the tooth length is not as small as what wouldbe desired (perhaps because the manufacturing technique, chosen for itscost effectiveness, is incapable of achieving a smaller length ofadjacent teeth), it is nevertheless possible to deliver amounts of drugcorresponding to an advance of half of the length of one of the teeth33,34, thereby halving the minimum deliverable volume.

[0106]FIG. 6 shows the device of FIG. 1 in operation at the completionof gas generation, and before the lever 19 has begun its return stroke.Thus, it can be seen that gas generation chamber 25 has expanded bypushing the diaphragm 24 outwards, and the lever 19 is thus pivoted onits axis 20 against the force of the return spring 29. When the lever 19is driven back to the FIG. 1 position, a small volume of liquid drug 13will be forced from the cartridge 12.

[0107] Because the device of FIG. 1 delivers small volumes in a stepwisefashion, it is possible to achieve an extremely low delivery rate. Forexample instead of operating in 5-minute cycles, the gas generator 25could be activated for 1 minute as previously described and thenswitched off for 59 minutes to give cycles of one hour duration. Unlikeother gas-driven devices which cannot achieve these long-term low-volumerates because of pressure losses in the system, the device 10 of thepresent invention does not require a system pressure to be maintainedabove atmospheric pressure.

[0108] As can be seen from FIGS. 1 and 6, the volume of the gasgeneration chamber 25 is small relative to the size of the device. Thisminimises variations in the volume of gas per stroke, and helps ensure aconstant delivery rate. Preferably, the device 10 will generate inexcess of 10-30% volume of gas over the required amount on each strokeso that the device can compensate of variations due to temperature,atmospheric pressure, materials used, etc. (The device will never drivethe ratchet 10-30% further than necessary, since the ratchet can onlymove in fixed steps.) This extra gas is stored as an overpressure in thesystem and is of course released during the venting part of the cycle.

[0109]FIG. 7 shows a cross-sectional side view of a second alternativeembodiment of the present invention, indicated generally at 50. Thedevice 50 is similar in most respects to the first embodiment shown inFIG. 1. In the device of FIG. 7, however, the pawl 51 is not split intotwo halves, so that it advances the ratchet bar 52 by full steps equalto the tooth length (“L”). In all other respects the device 50 isidentical to the device 10 of FIG. 1. It can be seen from FIG. 7 thatthe needle 53 of the device 50 (as with the FIG. 1 device) is bent at90° to the axis of the cartridge 54.

[0110] The device 50 of FIG. 7 is shown before use. A protective sheath55 is provided on the needle 53 and a displaceable lower cover 56 ishinged to the main housing 57 by a hinge (not shown). The displaceablelower cover 56 and the main housing 57 are prevented from movingrelative to one another by a safety tab 58. The lower surface 61 of thedisplaceable cover 56 is covered by a contact adhesive which isprotected before application to the user by a protective liner 60. Theliner 60 has a pull tab 59 to ease removal of the liner by the userimmediately before application of the device 50.

[0111] Before use, the protective sheath 55 is removed as indicated inFIG. 8 by grasping and pulling the pull tab 59. This also causes therelease liner 60 to be pulled away revealing the contact adhesive on thelower surface 61 of the displaceable cover 56. The lower surface 61 isadhered to the user's skin. Then, the safety tab 58 is pulled away fromthe device 50 as shown in FIG. 9.

[0112] As shown in FIG. 10, the main housing 57 is then pressed towardsthe skin whereupon it snaps towards the displaceable cover 56. Theneedle 53 projects beyond the lower surface 61 to penetrate into theskin for subcutaneous drug delivery.

[0113] The delivery mechanism is then actuated, either by the user, ormore preferably, in automatic fashion by the microprocessor. Uponactivation either manually or automatically, the ratchet bar 52 isadvanced by the pawl 53 in stepwise manner as described above withregard to the operation of the first embodiment as shown in FIG. 1.

[0114] When delivery is completed (see FIG. 11) the user can see thepiston 62 through an aperture 63 in the main housing 57 as shown in FIG.11. The main housing 57 is then pulled away from the skin whereupon itsnaps away from the displaceable cover 56 and locks in this position bya locking mechanism (described in more detail in our U.S. ProvisionalApplication No. 60/045,745) which prevents further actuation of thedevice, i.e. prevents the needle 53 from projecting beyond thedisplaceable cover 56 due to further relative movement of the mainhousing 57 and the displaceable cover 56.

[0115] In FIG. 12 there is indicated, generally at 70, a furtherembodiment of a device according to the invention. In the illustrationof this embodiment, only those details necessary to understand thedifferences relative to the devices of the first and second embodimentsare shown, and thus the gas generation mechanism, for example is notshown.

[0116] In the device of FIG. 12, the ratchet bar has been replaced by ahelical spring 71. A lever 72 is caused to reciprocate in identicalmanner to that previously described. A pair of resilient reciprocablefingers 73 are mounted on the lever 72 and reciprocate as the leverreciprocates. These reciprocable fingers 73 are inclined in thedirection of movement of the piston 74 as it empties the cartridge 75.Thus, when they move in the direction in which they are inclined theytend to grip and push the coils of the helical spring 71 forward. As thehelical spring 71 moves forward it slips past a pair of resilient fixedfingers 76 mounted directly in front of the reciprocable fingers 73, andinclined in identical manner.

[0117] When the lever 72 moves away from the piston 74 (as the gasgenerator generates the gas) the helical spring 71 is prevented frommoving back because it is gripped by the fixed fingers 76. Thereciprocable fingers 73 thus slip over the coils of the helical spring71. When the lever 72 reverses its travel again the helical spring 71 isagain gripped and pushed forward by the reciprocable fingers 73.

[0118]FIG. 13 shows a sectional side view of the device taken along theline XIII-XIII (in FIG. 12), in which the fixed fingers 76 and helicalspring 71 are visible.

[0119] Thus, the arrangement of reciprocable fingers 73 and fixedfingers 76 act as a pawl and the helical spring 71 acts as a ratchet,such that on each reciprocation of the lever 72, the helical spring 71advances by an amount equal to a set number of coil diameters.Accordingly, as with previously described embodiments, preciselycontrolled delivery rates are achievable, and in particular, extremelylow volume delivery rates are possible with this invention.

[0120] While there is a tendency for the helical spring 71 simply tostretch between the reciprocable fingers 73 and the fixed fingers 76,this tendency can be overcome by choosing the correct stiffness (forboth sets of fingers). Furthermore, the closer together the reciprocablefingers 73 and fingers 74 are mounted, the less likely the helicalspring 71 is to stretch, since the force is spread over fewer coils.

[0121] One advantage of this embodiment is that because the helicalspring 71 is curved within the device 70, it does not have to projectdirectly out of the cartridge 75 and thus a shorter device can berealised, or the shape of the device can be varied as required.

[0122] A further embodiment of the present invention is shown incross-sectional plan view in FIG. 14. The device, indicated generally at80, is in many respects identical to the device of FIG. 1 but differs inthat as well as the gas-driven lever 81, a second manual lever 82 isprovided. Manual lever 82 is mounted on a common axis 83 with gas-drivenlever 81, as can be seen referring additionally to FIG. 15. Manual lever82 passes under the ratchet bar 84 and also carries a second pawl 85.Both the upper surface 86 and lower surface 87 of ratchet bar 84 areprovided with ratchet teeth, so that either gas-driven lever 81 ormanual lever 82 can drive the ratchet bar 84 forward.

[0123] Thus, in normal operation, gas-driven lever 81 will drive thedrug from the cartridge 88, and in this mode, the ratchet bar 84 simplyslides past the pawl member 85 on manual lever 82 as describedpreviously. However, if a bolus dosage of drug is required at any pointin time, the manual lever 82 can be actuated to advance the ratchet bar84 by a predetermined number of teeth. Referring to FIG. 14, the manuallever 82 can be seen to have an adjustable threaded locking member 89which determines the extent of travel of the manual lever 82, and hencethe volume of the bolus delivery. In FIG. 14, the lever 82 is preventedfrom travelling because the threaded member 89 is fully torqued, andthis locks the lever 82 preventing it from being actuated. However, ifthe threaded member 89 is partially torqued and thereby partiallywithdrawn from the housing in the axial direction, the lever 82 is freeto move inwards by an amount equal to the distance of axial travel ofthe threaded member 89. The lever 82 can then be actuated by depressingthe threaded member 89. The degree of travel of the lever 82 isdetermined by the extent to which the threaded member 89 is turned, andby providing marked gradations on the threaded member 89 one can givethe user visual control over the volume delivered in such a bolusdosage.

[0124] The movement of the ratchet bar 84 under the action of the secondpawl 85 is independent of the primary pawl-and ratchet mechanism. Thus,the second pawl 85 will, when actuated manually, advance the ratchet bar84 by a whole number of steps. When advanced in this way, the ratchetbar 84 slides under the pawl member 90 on gas-driven lever 81, but thishas no effect on the basal delivery rate or on the operation of thegas-driven delivery mechanism 80. Thus, each individual ratchetmechanism is independent of the other, and bolus delivery can take placeagainst the background basal rate without complication.

[0125]FIG. 16 is a graph of typical results achieved in a test of adevice according to the invention, of the design shown in FIG. 1. Thegraph shows two lines, namely the cumulative delivery of drug againsttime (the stepwise steadily ascending line), and the delivery pressureagainst time (the line consisting of a succession of sharp peaks andtroughs).

[0126] It can be seen that the device was tested over an 80 hour period(more than 3 days) and delivered just under 1.35 grams of drug solutionin this time. This gives a delivery rate of less than 17 kg/hour.Furthermore, this delivery rate is absolutely constant, i.e. shows nodeviation from a straight line. Accordingly, the device of FIG. 1 has adelivery rate whose accuracy is unmatched in the prior art, particularlyfor extremely slow delivery rates.

[0127]FIG. 17 shows a portion of the graph of FIG. 16 in greater detail,over a five hour period in the middle of the test. It can be seen thatthe pressure on each cycle immediately shoots up to a maximum, and thenslowly falls off as gas is released through the silicone membrane.

[0128] It can be seen that the delivery overpressure reaches over 400mbar (0.4 atm or 40 kPa) on each cycle, and this assists in providing aconstant delivery rate, since any minor needle blockages will be forcedout, and variations in blood pressure (when intravenous delivery iseffected will have a negligible effect on the delivery rate. This is tobe contrasted with other low volume pumps which generally achieve lowdelivery rates with low delivery pressures.

[0129] A further alternative embodiment is illustrated in FIG. 18. Thedevice, indicated generally at 100, has a housing 101 containing aninternal needle 102 connected via a length of flexible tubing 103 to adelivery needle 104 (seen in sectional side view in FIG. 19). As withpreviously illustrated embodiments, delivery needle 104 is protected bya sheath 105 before use. Internal needle 102 is also protected by asheath 106 which is provided with a tab 107 extending the length of aninternal bore 108 to the exterior of the housing 101.

[0130] Flexible tubing 103 is carried on a ratchet bar 109 which can bedriven to move the internal needle 102 in the direction of the internalbore 108. It can be seen from FIG. 19 that a leaf spring 110 acting as apawl is carried on a lever 111 to drive the ratchet bar in the mannerpreviously described. Referring back to FIG. 18, the lever 11 is drivenby the expansion and contraction of an electrolytic cell 112 which ispowered by batteries 113.

[0131]FIG. 20 shows a step in the preparation of device 100 for use. Theinternal sheath 106 has been removed and is no longer visible, therebyexposing internal needle which is in the centre of a cylindrical cup114. A drug cartridge 115 is provided in the form of a cylindricalcontainer 116 sealed at its open end 117 by a piston 118 slidablyreceived in the container 116. Bore 108 is dimensioned to receivecartridge 115, and a pair of resilient projections 119 inside the bore108 hold the cartridge in place when it is pushed home within the bore.

[0132]FIG. 21 shows the device 100 when the cartridge 115 has beenpushed home. Internal needle 102 penetrates piston 118, such that theinternal needle 102 is in fluid communication with the drug inside thecartridge 115. Thus, movement of the ratchet bar 109 into the cartridge115 causes the piston 118 to be pushed along the length of the cartridge115, and thereby pump drug through the internal needle 102 and flexibletubing 103 to the delivery needle 104. As the internal needle 102 moveswith the piston into the cartridge 115, the flexible tubing 103 ispulled behind, thereby maintaining communication between internal needle102 and delivery needle 104.

[0133] Another advantage of flexible tubing 103 is that it enablesdelivery needle 104 to be mounted at any point on the device, and thusthe placement of the delivery needle in this embodiment is notconstrained by the design of the other features.

[0134] Although the electrolytic cell 112 in device 100 operates inexactly the same manner as the cells in previously describedembodiments, the configuration of lever 111 and the pivot 119 on whichit is mounted causes pawl 110 to advance ratchet bar 109 during the gasgeneration step rather than during the venting step.

[0135] A further embodiment is shown in FIGS. 22-26. In FIG. 22, theembodiment 120 comprises a housing 121 containing a cartridge 122 filledwith a drug 123. The cartridge 122 is provided with a needle 124 fordelivery of drug 123 to a patient. The cartridge 122 includes a piston125 which is slidably received in the cartridge 122. The piston has anouter recess 126 for receiving a needle sterility cover 127. The needlesterility cover 127 covers a first end 128 of the needle 124 andprevents contamination thereto. A second end 129 of the needle 124 isconnected to a length of tubing 130. The tubing 130 has a first end 131and a second end 132, as shown in FIG. 24. The tubing 130 second end 132is secured within an activation assembly 163. A second needle 134 isalso secured to the activation assembly 163. A drug pathway 133 ismachined into the activation assembly 163, and the tubing 130 and secondneedle are secured within the activation assembly by means of anadhesive, preferably an ultra-violet bonding agent. A second needlesterility cover 135 is slidably received on the exterior end 136 of thesecond needle 134. Prior to use, the second needle sterility cover 135is manually removed so as to uncover the exterior end 136 of the secondneedle 134 so that it is ready for penetration into the user's skin.

[0136] Returning now to FIG. 22, the piston 125 and needle 124 aremounted on a ratchet bar 137 having a multitude of stepped increments138 thereon. The ratchet bar 137 is moved by a leaf spring 139 integralwith a reciprocating lever 140. The lever 140 is mounted on an axis 141and has a return spring 142 that applies constant pressure to the lever139 in a single direction. The lever 139 rests against a gas generatorsub-assembly 144 and moves in response to pressure differentiationcreated therein.

[0137] The gas generation sub-assembly 144, includes a pair ofelectrolytic cells 145, 146, as shown in FIG. 26. The first cell 145 isthe propulsion cell. The propulsion cell 145 has a first diaphragm 147made of a low permeability material, such as bromo-butyl, ethylenepropylene, or EPDM. The lever 140 rests against the first diaphragm 147.The second cell 146 has a second diaphragm 148 thereon. The seconddiaphragm 148 is made of a high permeability material, such as siliconerubber. The first cell 145 has a hose 149 extending from the side of thefirst cell 145 to above the surface of the top of the second cell 146. Agap 143 is created between the end of the hose 149 and the top surfaceof the second cell 146. The cells 145, 146 are activated with electricalenergy from batteries 150.

[0138] Additional components in the present embodiment 120 include adrug cartridge recess 151, as shown in FIG. 23. The drug cartridge has asleeve 152 for receiving and supporting the cartridge 122 and ensuringsafe and accurate operation of the device 120. The sleeve 152 isslidably received into the recess 151. The sleeve 152 has a lip 153 onthe exterior at the insertion end 154 of the sleeve. The recess 151 hasa shelf 155 for receiving the lip 153 of the sleeve when the cartridge122 is fully inserted, as shown in FIG. 21. A cartridge receivingchannel 156 is located within the housing 121 and is proximate to therecess 151. The channel provides further support for the cartridge whenit is inserted within the device 120. The channel includes an outer edge157, an inner edge 158 and an arched portion 159. The outer and inneredges are parallel and align with the cartridge recess to guide andsupport the cartridge 122 upon insertion and during use. The archedportion 159 of the channel is integral with the inner edge 158 and iscurved away from the cartridge and ratchet assembly. Prior to operation,the arched portion 159 rests against a depressable button 160 that ispart of the gas generating sub-assembly 137. The button 160 has apuncturing device on the inner surface thereof. When depressed, thepuncturing mechanism breaks a seal 161 of the compartment 162 containingthe chemical entity used in the electrolytic cells 145, 146 of the gasgenerating sub-assembly 144, as shown in FIG. 22. The chemical entity istypically potassium chloride, and in the present embodiment, it ispreferably in a less viscous form so as to enable the liquid to move togaseous form more quickly.

[0139] With this design, in the event the electrical connection is madeprior to use, gas generation in the sub-assembly 144 is not possiblebecause the gas generating chemical is sealed within its compartment162. In addition, this design prevents operation of the device unlessthe drug cartridge is fully engaged. The arched portion 159 is locatedso as to only be deflectable by the drug cartridge when the cartridge isin its fully inserted position. Thus, ensuring that the full dosage ofthe drug will be delivered.

[0140]FIG. 24 shows a cross-sectional view of manual activation assembly163 along line A-A. The activation assembly 163 includes a spring loadedstart button 164 which is slidably received within a button channel 165.The button 164 is maintained in an outward position by means of ahelical spring 166, located and supported in the button channel 165. Thehelical spring 166 is loaded both axially and torsionally within thebutton channel 165. FIG. 25 is a cross-sectional view of the activationassembly along line B-B, which shows a pin 169 which moves within agroove 170 in the button channel 165 from a first, pre-operationalposition [shown as position 169A], to a second, operational position[169B], to a third, locked position [169C].

[0141] Returning to FIG. 24, the button 164 has a finger 167 extendingtherefrom. The finger 167 is located directly above a deflectableelectrical contact 168. When the button 164 is depressed, the finger 167contacts the electrical contact 168 and causes it to deflect, thuscausing electrical communication between the contacts and initiatingoperation of the device 120.

[0142] In operation, the embodiment 120, shown in FIG. 22, is suppliedwith a drug cartridge 122. The cartridge 122, filled with drug 123 isfully inserted into the cartridge recess 151. When the cartridge 122 isfully inserted, the lip 153 of the sleeve 152 lockably engages with theshelf 155 and prevents the cartridge 122 from being removed. As thecartridge 122 is inserted, the needle sterility cover 127 engages withthe piston outer recess 126, and the tip of the needle pierces theneedle sterility cover 127 and piston 125 and moves into the interior ofthe cartridge, as shown in FIG. 23. The travel of the cartridge endswhen the sleeve lip engages with the shelf and the inner and outer edgesof the channel. As the cartridge is fully inserted, the cartridge edgecontacts the arched portion of the channel 156 causing it to deflectaway from the cartridge. Such deflection applies pressure to thedepressable button which depresses and pierces the container of chemicalused to generate the gas within the electrolytic cells. The device 120is then applied by the user or health care worker to the skin.

[0143] The device is then activated when the start button 164 isdepressed causing the finger 167 to contact the electrical contact 168thus closing an electrical circuit which initiates gas generation in thesub-assembly. Once the button 164 is depressed, the torsional force ofthe helical spring 166 prevents the button from springing back up andlocks the button, and second needle 134 in position [169B] duringoperation, as shown in FIG. 25.

[0144] When the cells 145, 146 are activated with electrical energy fromthe batteries 150, both cells begin to generate gas. The first cell 145builds pressure quickly because of the low permeability of the firstdiaphragm 147, as shown in FIG. 26A. However, pressure is releasedthrough the hose and exits into the atmosphere within the housing 121.As pressure builds in the second cell 146, the second diaphragm 148deforms outwardly, closing the gap 143 between the hose and the topsurface of the second cell, as shown in FIG. 26B. When this is closed,the gas from the first cell can no longer escape into the atmosphere,causing the first diaphragm to elastically deform outwardly. Thisdeformation applies pressure to the lever 140, as shown in FIG. 26C.When pressure is applied on the lever, it causes the leaf spring to movefrom a first stepped increment 138A to a second increment 138B. Thismovement causes the piston 125 to move further along the length of thedrug cartridge 122, decreasing the volume of drug 123 in the cartridgeand moving such drug into the patient via the needle 124.

[0145] Once pressure has built sufficiently in the first cell 145 so asto move the leaf spring incrementally forward, gas generation in thecells is deactivated so as to begin to decrease pressure within thecells. As the pressure in the second cell decreases, the seconddiaphragm flattens out, thereby re-creating the gap 143 and allowing airto bleed quickly from the first cell, as shown in FIG. 26D.

[0146] The gas-generation sub-assembly is designed in such a way so asto provide maximum efficiency in the cycle of moving the leaf springfrom a first increment 138A to a second increment 138B. The lowpermeability of the first diaphragm 147 allows the pressure to build inthe first cell 145 and thus results in quick deformation of thediaphragm and movement of the reciprocating piston 143. However, theintegration between the first and second cells, 145, 146, is importantin order to quickly release the pressure within the first cell 145 afterthe leaf spring has been moved forward. The hose 149 between the firstand second cell connects the two cells during deflection and providesfirst for the build up of pressure. After the pressure within the firstcell builds sufficiently move the reciprocating piston, the electricalconnection to the batteries 150 is disconnected, or decreased. Thiscauses a rapid decrease in the pressure of the second cell 146 becausemuch of the gas created escapes through the second diaphragm. As thepressure in the second cell 146 declines, the second diaphragm losesheight and recreates the gap 143, thus allowing gas from the first cellto quickly bleed off and return to a low pressure state to begin thenext cycle. It should be noted that it is possible to maintain a minimumcurrent level within the cells in order to keep a minimum level ofpressure in the cells so as not to start the build up of pressure from alower point than necessary, thus maximizing the efficiency of the cycletime. In one application, the current needed during the gas generationportion of the cycle may range from 5-7 milliampers, and the current tomaintain the minimum level of pressure may range from 30-50 microampers.This cell design has enabled the cycle time to decrease from 20 minutesto 5 minutes in the present embodiment.

[0147] The length between activating and deactivating the electrolyticcells may be controlled by means of a microprocessor, along with the useof different diaphragm materials. Thus, the cycle time to move the leafspring a single increment may be adjusted depending upon the deliveryrate desired. Moreover, the number and size of increments may be alteredto provide further flexibility in the delivery rate.

[0148] When the delivery is complete, the helical spring 166 which istorsionally loaded, forces the pin 169 to move from the operationposition [169B] to a locked post-operational position [169C]. Thiscauses the entire activation assembly to retract and the exterior end136 of the second needle 134 to be recessed into the housing, therebyavoiding any accidental injury or attempted further use of the device120.

[0149] It should also be noted that in the present embodiment 120, thenumber of sterile components has been minimized so as to eliminate theneed to sterilize the entire device. The following components aresterilized as an assembly prior to being assembled into the device. Thesterilized sub-assembly includes the needle sterility cover 127, theneedle 124, the tubing 130, the start button 164, the drug pathway 133,the second needle 134, and the penetrating needle sterility protector135.

[0150] It will be appreciated that the embodiments discussed above arepreferred embodiments, falling within the scope of the appended claims,and that various alternative embodiments are contemplated. For example,while leaf and coil springs were discussed in the preferred embodiments,it is anticipated that other types of springs may also be used.

[0151] The term “drug” used herein includes but is not limited topeptides or proteins, hormones, analgesics, anti-migraine agents,anti-coagulant agents, narcotic antagonists, chelating agents,anti-anginal agents, chemotherapy agents, sedatives, anti-neoplastics,prostaglandins, antidiuretic agents, anti-sense agents,oligonucleotides, mucosal vaccines, gene-based medicines andpermeability and enhancing agents.

[0152] Typical drugs include peptides, proteins or hormones such asinsulin, calcitonin, calcitonin gene regulating protein, atrialnatriuretic protein, colony stimulating factor, betaseron,erythropoietin (FPO), interferons such as α, β or γ interferon,somatropin, somatotropin, somastostatin, insulin-like growth factor(somatomedins), luteinizing hormone releasing hormone (LHRH), tissueplasminogen activator (TPA), growth hormone releasing hormone (GHRH),oxytocin, estradiol, growth hormones, leuprolide acetate, factor VIII,interleukins such as interleukin-2, and analogues thereof; analgesicssuch as fentanyl, sufentanil, butorphanol, buprenorphine, levorphanol,morphine, hydromorphone, hydrocodone, oxymorphone, methadone, lidocaine,bupivacaine, diclofenac, naproxen, paverin, and analogues thereof;anti-migraine agents such as sumatriptan, ergot alkaloids, and analoguestherof; anti-coagulant angents such as heparin, hirudin, and anloguestherof; anti-emetic agents such as scopolamine, ondansetron,domperidone, metoclopramide, and analogues thereof; cardiovascularagents, anti-hypertensive agents and vasodilators such as diltiazem,clonidine, nifedipine, verapamil, isosorbide-5-mononitrate, organicnitrates, agents used in treatment of heart disorders, and analoguesthereof; sedatives such as benzodiazepines, phenothiozines, andanalogues thereof; chelating agents such as deferoxamine, and analoguesthereof; anti-diuretic agents such as desmopressin, vasopressin, andanalogues thereof; anti-anginal agents such as nitroglycerine, andanalogues thereof; anti-neoplastics such as fluorouracil, bleomycin, andanalogues thereof; prostaglandins and analogues thereof; andchemotherapy agents such as vincristine, and analogues thereof.

[0153] Other drugs include antiulcer agents, such as but not limited tocimetidine, and ranitidine; antibiotics; anticonvulsants;antiinflammatories; antifungals; antipsychotics; corticosteroids;immunosuppressants; electrolytes; nutritional agents and vitamins;general anesthetics; antianxiety agents, such as but not limited tocompazine; and diagnostic agents.

What is claimed is:
 1. A drug delivery device comprising: a housingcontaining a drug reservoir; means for facilitating expulsion of drugfrom the drug reservoir; a mechanism in communication with thefacilitation means, operable to undergo incremental advancement andthereby drive the drug from the reservoir; a member operativelyassociated with the mechanism to cause the incremental advancement ofthe mechanism as the member moves in a first direction; and gasgenerating means located within the housing and operable to expand in achamber, the member being in transmission relation to the chamber,whereby the member is driven by the movement of the chamber to advancethe mechanism and thereby drive the drug from the reservoir inincremental fashion.
 2. The drug delivery device according to claim 1,wherein the mechanism in communication with the facilitation meanscomprises a ratchet.
 3. The drug delivery device according to claim 1,wherein the member moves in a reciprocable fashion.
 4. The drug deliverydevice according to claim 3, wherein the movement of the reciprocablemember causes the stepwise advancement of the mechanism.
 5. The drugdelivery device according claim 3, wherein the member is connected to awall of the chamber, whereby the reciprocable movement of the member isdriven by the expansion and contraction of the chamber.
 6. The drugdelivery device according to claim 1, wherein the chamber is elasticallybiased to revert to a contracted state, and wherein a venting means isprovided to enable contraction of the chamber after gas generation hasexpanded the chamber.
 7. The drug delivery device according to claim 6,wherein the venting means is passive and allows escape of gastherethrough when the chamber is pressurised relative to atmosphericpressure.
 8. The drug delivery device according to claim 7, wherein thegas generator is adapted to generate gas at a rate higher than the rateat which venting occurs, whereby when the gas generator is active, thechamber becomes pressurised and expands, and when the gas generator isinactive, the venting means causes depressurisation and contraction ofthe chamber.
 9. The drug delivery device according to claim 7, whereinthe venting means comprises a permeable or semi-permeable member. 10.The drug delivery device according to claim 9, wherein the member is asilicone membrane.
 11. The drug delivery device according to claim 1,wherein the mechanism is caused to advance as the chamber undergoesexpansion.
 12. The drug delivery device according to claim 1, whereinthe mechanism is caused to advance as the chamber undergoes contraction.13. The drug delivery device according to claim 1, wherein the membercomprises a lever extending between the chamber and the mechanism. 14.The drug delivery device according to claim 1, wherein the mechanismcomprises a rigid ratchet element having spaced formations on a surfacethereof.
 15. The drug delivery device according to claim 14, wherein theformations have a sawtooth cross section.
 16. The drug delivery deviceaccording claim 14, wherein the formations are grooves on a surface ofthe rigid ratchet element.
 17. The drug delivery device according toclaim 14, wherein the mechanism includes a pawl carried on the member,the pawl being adapted to make ratcheting engagement with the formationson the rigid ratchet element.
 18. The drug delivery device according toclaim 17, wherein the pawl is resiliently biased against the formationson the rigid ratchet element.
 19. The drug delivery device according toclaim 18, wherein the pawl is in the form of a substantially flat springan end of which bears against the formations on the rigid ratchetelement.
 20. The drug delivery device according to claim 18, wherein theformations are regularly spaced along the rigid ratchet element, andwherein the pawl comprises a pair of pawl members resiliently biasedagainst the rigid ratchet element at different points along the lengthof the rigid ratchet element, the axial distance between the pair ofpawl members being different to the axial distance between successiveformations.
 21. The drug delivery device according to claim 20, whereinthe distance between successive formations is twice the distance betweenthe pawl members.
 22. The drug delivery device according to claim 18,wherein the formations are regularly spaced along the rigid ratchetelement, and wherein the pawl comprises three or more pawl membersresiliently biased against the rigid ratchet element at regularintervals along the length of the rigid ratchet element, the axialdistance between each successive pair of pawl members being different tothe axial distance between successive formations.
 23. The drug deliverydevice according to claim 22, wherein the distance between successiveformations is given by the number of pawl members multiplied by thedistance between each successive pair of pawl members.
 24. The drugdelivery device according to claim 20, wherein the pawl is in the formof a resilient member which terminates in the pawl members which are inthe form of a plurality of fingers biased against the ratchet element.25. The drug delivery device according to claim 1, wherein the mechanismcomprises a helical spring and one or more fingers which make aratcheting engagement with the coils of the spring.
 26. The drugdelivery device according to claim 25, wherein one or more fixed fingersare mounted in fixed position relative to the housing, and one or morereciprocable fingers are mounted on the mechanism, such that when theone or more reciprocable fingers move in a first direction they engagethe coils of the helical spring to drive the helical spring in the firstdirection, and when the one or more reciprocable fingers move in anopposite direction, the one or more fixed fingers engage with and holdthe coils of the helical spring preventing it being driven back in thesecond direction, whereby the fixed and reciprocable fingers co-operateto drive the helical spring in one direction only.
 27. The drug deliverydevice according to claim 26, wherein the or each finger is inclined inthe first direction.
 28. The drug delivery device according to claim 26,wherein the position of the one or more fixed fingers relative to theone or more reciprocable fingers is such that the helical spring isdriven by the reciprocable fingers towards the fixed fingers.
 29. Thedrug delivery device according to claim 26, wherein the minimum distancebetween the fixed and reciprocable fingers, respectively, is not greaterthan ten times the distance between adjacent coils of the helical springwhen the helical spring is in a relaxed position.
 30. The drug deliverydevice according to claim 29, wherein the minimum distance between thefixed and reciprocable fingers, respectively, is not greater than fivetimes the distance between adjacent coils of the helical spring when thehelical spring is in a relaxed position.
 31. The drug delivery deviceaccording to claim 30, wherein the minimum distance between the fixedand reciprocable fingers, respectively, is not greater than twice thedistance between adjacent coils of the helical spring when the helicalspring is in a relaxed position.
 32. The drug delivery device accordingto claim 31, wherein the minimum distance between the fixed andreciprocable fingers, respectively, is approximately equal to thedistance between adjacent coils of the helical spring when the helicalspring is in a relaxed position.
 33. The drug delivery device accordingto claims 1, wherein the mechanism comprises a flexible ratchet elementwhich is sufficiently stiff to drive medicament from the chamber whendriven by the member, and sufficiently flexible to be bent before itmeets the member, whereby the overall length of the device is reducedrelative to a device in which a rigid ratchet element protrudes linearlyfrom the mechanism before use.
 34. The drug delivery device according toclaim 33, wherein the mechanism comprises two or more co-operatingflexible ratchet elements which are individually sufficiently flexibleto be bent before they meet the member but when joined together aretogether sufficiently stiff to drive medicament from the chamber whendriven by the member.
 35. The drug delivery device according to claim34, wherein the two or more co-operating flexible ratchet elements arebent away from one another before they meet the member.
 36. The drugdelivery device according to claim 1, further comprising electroniccontrol means for controlling the delivery rate.
 37. The drug deliverydevice according to claim 36, wherein the electronic control meanscomprises a timing mechanism which alternately energises andde-energises the gas generating mechanism for controlled periods. 38.The drug delivery device according to claim 36, wherein the electroniccontrol means is programmable for different delivery programs.
 39. Thedrug delivery device according to claim 1, further comprising means formanually adjusting the delivery rate.
 40. The drug delivery deviceaccording to claim 39, wherein the member reciprocates to cause theincremental advancement of the mechanism and the means for manuallyadjusting the delivery rate comprises means for limiting the travel ofthe member, whereby the volume of drug delivered on each reciprocatingstroke is controllable.
 41. The drug delivery device according to claim39, wherein the means for manually adjusting the delivery rate comprisesmeans for delivering a bolus dose of drug.
 42. The drug delivery deviceaccording to claim 41, wherein the means for delivering a bolus dose ofdrug comprises means for manually advancing the mechanism by one or moresteps independently of the gas generating mechanism.
 43. The drugdelivery device according to claim 42 wherein the means for manuallyadvancing the mechanism comprises means for manually advancing the leverextending between the chamber and the mechanism, operable from theexterior of the housing.
 44. The drug delivery device according to claim43, wherein the mechanism comprises a ratchet and wherein the means formanually advancing the mechanism comprises a pawl which is manuallyreciprocable from the exterior of the housing.
 45. The drug deliverydevice according to claim 1 wherein the gas generation means comprises:a first gas generation chamber having a housing, gas generation means,and a first diaphragm made of a low gas permeable material; a second gasgeneration chamber having a housing containing gas generation meanstherein and a second diaphragm made of a high gas permeable material;and means for controllably venting excess gas from the first chamber.46. The device of claim 1 wherein the drug reservoir is in the form of adrug cartridge.
 47. The device of claim 46 further comprising means forpreventing activation of the gas generating means until the drugcartridge is operational position within the housing.
 48. The device ofclaim 47 wherein the prevention means comprises a sleeve for receiving adrug cartridge, the sleeve slidably received by a recess in the housing,and a lip on the exterior edge of the sleeve for engagement with aninterior surface of the housing,
 49. A method of delivering drug to apatient comprising the steps of: affixing a drug delivery device to thesurface of the patient's skin, the drug delivery device comprising: ahousing containing a drug reservoir; means for facilitating expulsion ofdrug from the drug reservoir; a mechanism in communication with thefacilitation means, operable to undergo incremental advancement andthereby drive the drug from the reservoir; a member operativelyassociated with the mechanism to cause the incremental advancement ofthe mechanism as the member moves in a first direction; and gasgenerating means located within the housing and operable to expand in achamber, the member being in transmission relation to the chamber; andactivating the device whereby the member is driven by the movement ofthe chamber to advance the mechanism and thereby drive the drug from thereservoir in incremental fashion.
 50. The method according to claim 45,wherein the mechanism in communication with the facilitation meanscomprises a ratchet.
 51. The method according to claim 45, wherein themember moves in a reciprocable fashion.
 52. The method according toclaim 47, wherein the movement of the reciprocable member causes thestepwise advancement of the mechanism.
 53. The method according to claim47, wherein the member is connected to a wall of the chamber, wherebythe reciprocable movement of the member is driven by the expansion andcontraction of the chamber.
 54. The method according to claim 45,wherein the drug reservoir is provided separately from the housing, andthe method further comprises the step of adding the drug reservoir tothe housing before use.
 55. The method according to claim 45, whereinmeans are provided for advancing the mechanism manually, and the methodfurther comprises the step of manually advancing the mechanism todeliver a bolus dose of drug to the subject.